New Drugs for Treating Lung Infection

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New Drugs for Treating Lung Infection*

Patrick E. Nolan, M.D.; and]ohn B. Bass, M.D., F.C.C.~

Pneumonia-an infectious disease characterized by inflammation of the lungs and constitutional disturbance of varying intensity. The f~r terminates abruptly by crisis. Secondary infectioo processes are common. An organism, the Diplococcus pneumoniae, is invariably found in the diseased lung . . . pneumonia is a self-limited disease and runs its course uninfluenced by medicine. William Osler, 1892

In 1988, the care of the patient with pneumonia is complicated not only by an expanding range of pathogens, but also by a bewildering growth of new antimicrobial agents capable of halting the disease course. Although penicillin and erythromycin still fonn the mainstays of therapy for most pneumonia, the changing clinical settings mandate a critical look at new drugs which may favorably influence the considerable morbidity and mortality still associated with this classic infectious disease. The aging population, the longer survival of the critically ill and immunocompromised patient, the widespread use of antibiotics, the discovery of new pathogens and the epidemic of AIDS have all contributed to an expanding spectrum of lower respiratory pathogens. The increasing incidence of Gram-negative bacillary pneumonia, the increasing emergence of drug resistance not only in Hemophilus injluenzae but also in Streptococcus pneumoniae and the increasing need to consider opportunistic pathogens are factors which undermine the dominance of penicillin and erythromycin in our armamentarium against lung infection. The growth of new antimicrobial agents active in lung infection include the following: (1) expansion of the beta-Iactam class including new cephalosporins, carbapenems, and monobactams; (2) the combination of beta-Iactamase inhibitors with traditional antibiotics; (3) the development of the quinolone family of antibiotics; (4) newer antimycobacterial: and (5) antiviral agents. The newer drugs discussed in this article have not ·From the Department of Medicine, University of South Alabama College of Medicine, Mobile. (Ches' 1988; 94:1076-79) Reprint requests: Dr: Nolan, Cancer Center, Clinical Building Rm 428, Unioorsity of South Alabama, Mobile 36688 1076

been fully evaluated in prospective comparative studies, and although many are attractive because of their broad spectrum and superior pharmacokinetic profiles, they should not be thought of as simple alternatives to standard therapy The real value of these newer agents lies in their unique properties that allow application in special circumstances. BETA-LACTAMS:

CEPHALOSPORINS,

CARBAPENEMS,

MONOBACTAMS

Second Generation Cephalosporins The second generation cephalosporins of the cefamandole type have been popular choices for empiric therapy of community-acquired pneumonia. These second generation agents are characterized by specific substitutions at the HI side chain which protect the beta-Iactam ring of the cephalosporin nucleus from cleavage by beta-Iactamases. The spectrum of activity includes not only Streptococcus pneumoniae, but also Staphylococcus aureus, Hemophilus injluenzae, Klebsiella pneumoniae and oral anaerobes-important pathogens of the lower respiratory tract in patients compromised by old age, debility chronic obstructive pulmonary disease, or alcoholism. Although not a new cephalosporin, cefuroxime became available in the United States only after prolonged experience in Europe. It appears to have a number of advantages over cefamandole. It does not have the methyltetrazolethiole side chain which has been associated with prothrombin time prolongation and bleeding. It also has a half-life of 1.3 hours compared to 0.6 hours for cefamandole which allows every eight-hour dosing intervals. The major advantage is that it achieves excellent central nervous system penetration, unlike cefamandole, which may be especially important in the elderly or debilitated patient more likely to have pneumonia complicated by bacteremia and meningitis. Clinical trials! have shown excellent results in community-acquired pneumonia. Comparative studies have shown the superiority of cefuroxime compared to ampicillin- and equal efficacy to trimethoprimsulfamethoxazole." New Drugs for TreatingLung Infection (Nolan, Bass)

Third Generation Cephalosporins The aminothiazolyl cephalosporins such as cefotaxime, ceftizoxime, ceftriaxone, and ceftazidime are third-generation cephalosporins characterized by increasing Gram-negative activity as well as longer halflife. Although the clearest advantage of these third generation cephalosporins has been in the therapy of Gram-negative bacillary meningitis, they clearly are important agents in the therapy of Gram-negative bacillary pneumonia. The spectrum of activity which the third generation agents share with cefuroxime is activity against H influenzae, Escherichia coli, K pneumoniae, Enterobacter aerogenes, and Proteus mirabilis. In addition, these third generation agents show activity against Serratia sp, Morganella morganii, Providencia sp, and Citrobacter sp. Except for ceftazidime, activity against Pseudomonas aeruginosa is poor, Activity of the third generation agents against Staph aureus and Acinetobacter sp is unreliable. Clinical trials of the third generation agents in Gramnegative pneumonias of various types show efficacy between 60 and 100 percent with no clearcut advantage of any agent being demonstrated. Comparative studies against amoxicillin and doxycycline have shown the superiority of third generation agents in adult lower respiratory tract infection. Empiric use of one of the third generation cephalosporins would be appropriate in settings where Gram-negative pathogens were suspected. Monotherapy with one of these agents may be considered for Klebsiella sp, E coli, or H influenzae pneumonia. Combination therapy with an aminoglycoside should be employed for Pseudomonas, Serratia, or Enterobacter pneumonia, as well as in the patient with severe debility and immune suppression. Carbapenems The carbapenem class of antibiotics is characterized by substitution of carbon for sulfur in the dihydrothiazine ring of the cephalosporin nucleus. Imipenem is the first antibiotic in the carbapenem class. Imipenem is combined with cilastatin which blocks the renal metabolism of imipenem and is sometimes referred to as imipenem-cilastatin. The spectrum of activity is very broad and includes Staph aureus, P aeruginosa, and Bacteroides sp, as well as Strep pneumoniae, H influenzae, and Klebsiella sp. Clinical trials have shown excellent results in adult lower respiratory tract infections with imipenem used as monotherapy Small trials in cystic fibrosis patients have shown favorable responses. Of all the strains isolated from the lower respiratory tract in these trials, 93 percent showed in vitro sensitivity to imipenem. The exact role for imipenem therapy in pneumonia is not clear. Concern with the possibility of selection of multiresistant organisms should caution widespread empiric use. Per-

haps this drug should be reserved for proven infections with organisms resistant to other antibiotics. M onobactams

Another new variation in beta-lactam antibiotics has been the elimination of the second carbon ring from the chemical structure to leave the beta-lactam ring alone as a monocyclic compound. Aztreonam is the first antibiotic in the monobactam class. Contrary to the general trend of the newer agents, the spectrum of activity for aztreonam is relatively narrow and includes K pneumoniae, Proteus sp, E coli, and P aeruginosa. An aminothiazolyl side chain confers Gram-negative activity similar to the third-generation cephalosporins, and P aeruginosa activity is comparable to piperacillin or ceftazidime, The loss of the second carbon cycle eliminates Gram-positive and anaerobic activity Aztreonam has been used in lower respiratory tract infections in relatively small open clinical trials. The experience is excellent in Gramnegative bacillary pneumonia. Only three comparative trials have been performed-each comparing aztreonam with tobramycin monotherapy These demonstrate the superiority of aztreonam to tobramycin in Gram-negative bacillary pneumonia. 4 This may reflect the advantage of aztreonam over aminoglycosides in activity at the low pH and eH found in purulent lung tissue. No comparative trials have been performed against the aminothiazolyl cephalosporins or with combination therapy: An attractive but, as yet, unproven use for this drug would be as a substitute for aminoglycosides in combination therapy with another beta-Iactam. Because of the possibility of antagonism, however, in vitro evaluation of untested beta-lactam combinations should precede clinical application. Aztreonam has also been shown effective in treating lower respiratory tract infection with P aeruginosa in cystic fibrosis patients when used as monotherapybut experience is limited. Because of its narrow spectrum, this drug is not a good empiric agent when used alone, but in cases with an established Gramnegative etiology this promises to be an important drug. It should be noted that unlike imipenem which shares hypersensitivity reactions with other betalactams, there is good evidence that a history of penicillin or cephalosporin allergy does not preclude use of aztreonam. This is a unique narrow-spectrum and safe antibiotic. COMBINATION BETA-LAcrAMASE INHIBITORS

Another approach to the beta-Iactam theme has been the addition of so-called "suicide inhibitors"clavulanic acid and sulbactam-to more traditional beta-lactam antibiotics. The suicide inhibitors have a beta-lactam structure which selectively combine and inactivate the beta-Iactamases of Gram-positive and CHEST I 94 I 5 I NOVEMBER. 1988

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Gram-negative organisms. There are three currently available beta-Iactamase inhibitor combinations: amoxicillin-clavulanic acid, ticarcillin-clavulanic acid, and the combination ampicillin-sulbactam. Amoxicillin-clavulanic acid is available only in oral form. Clinical trials with amoxicillin-clavulanic acid have been very limited. Most of the adult patients in studies have had upper and not lower respiratory tract infections. Ticarcillin-clavulanic acid is a parenteral antibiotic with activity against Staph aureus, H injluenzae, and P aeruginosa, as well as anaerobes. Small open clinical trials have demonstrated the efficacy of ticarcillinclavulanate in lower respiratory infections. The most appropriate use may be in mixed infections where Staph aureus, P aeruginosa, and/or anaerobes are likely Caution is advised if microbiologic data suggest a single pathogen, eg, Staph aureus, or if susceptibility data show ticarcillin resistance, eg, some isolates of K pneumoniae or P aeruginosa. Ampicillin-sulbactam, another beta-Iactamase inhibitor, has a broad spectrum of activity It is less effective against P aeruginosa than ticarillin-clavulanic acid. Open clinical trials have demonstrated good results in community-acquired pneumonia. No comparative studies are available. QUINOLONES

The quinolone family of antibiotics are derivatives of nalidixic acid currently undergoing rapid development and appear to have an enormous potential for clinical utility There are a number of four-Huoroquinolones which have been marketed in the United States and Europe. Currently in the United States, ciproHoxacin appears to be the one with most direct applicability for use in lung infections. CiproHoxacin is a broad spectrum antibiotic. Activity includes most Gram-negative rods including Pseudomonas sp, H injluenzae, and Staph aureus including methicillin-resistant Staph aureus. A unique feature among all the newer agents is in vitro activity against Legionella pneumophila and Mycoplasma pneumoniae. Although ciprofloxacin has in vitro activity against the Pneumococcus, it is marginal and clearly inferior to penicillin or erythromycin. Most favorable clinical experience has been in cystic fibrosis, although at least four trials demonstrated excellent results using ciprofloxacin in community-acquired pneumonia. A recent study comparing ciprofloxacin to imipenem in 60 patients with severe clinical infection mostly of the respiratory tract showed comparable clinical and bacteriologic efficacy of the two agents. 5 CiproBoxacin should not be used for anaerobic infection, or in cases of pneumococcal pneumonia. Known Gram-negative pneumonia with H injluenzae, Pseudomonas sp, and Klebsiella sp could be treated with ciprofloxacin which 1078

has the advantage of oral administration. Empiric use should probably be reserved for exacerbations of chronic obstructive pulmonary disease. Theophylline levels may increase with the use of ciproHoxacin, and doses should be appropriately adjusted. Also, magnesium-containing antacids interfere with oral absorption and should be avoided. ANTI M YCOBACfE RIALS

Some tentative advances have been made in the therapy of resistant mycobacterial tuberculosis and in some nontuberculous mycobacterial infections. CiproHoxacin has shown in vitro activity against Mycobacteria sp and is currently undergoing study in combination therapy for Mycobacterium avium complex (MAC) infection in patients with AIDS. Clofazimine is an antileprosy agent which has had increased use in multidrug resistant M tuberculosis as well as MAC infection. Clinical trials have not shown conclusive results for either M tuberculosis or MAC. It is presently unclear where this fits into our antimycobacterial armamentarium. Rifabutine is a rifampin derivative which shows in vitro activity against M tuberculosis as well as MAC and M fortuitum. It has a longer half-life than rifampin and has shown in vitro activity against the HIV virus. Release for compassionate use in patients with mycobacterial disease associated with AIDS has shown marginal efficacy 6 Eighteen percent of patients with disseminated disease compared to 44 percent of patients with local disease showed improvements with rifabutine. It is not currently recommended for general clinical use. ANTIVIRALS

DHPG (dihydroxy-proxomethylguanine) or ganciclovir is an analog of acyclovir which demonstrates potent activity against CM~ Preliminary trials in bone marrow recipients and in AIDS patients with CMV pneumonitis have shown favorable virologic responses, although improvement in clinical outcome has been difficult to demonstrate. Approximately 25 percent of the 500 patients who have received DHPG under a compassionate use protocol have had pneumonia. Most patients have received 10 mg/kg/day in two divided doses for a period of two to three weeks. The CMV pneumonia has responded less well than retinitis or gastrointestinal disease although some clinical improvement has been observed in close to 60 percent of patients. Studies with DHPG have been Hawed by lack of placebo control as well as by lack of understanding of the natural history of CMV pneumonitis. About 40 percent of patients develop suppression of white blood cell counts and platelets. Close observation of blood counts and adjustments are frequently necessary in these patients. New Drugs for Treating Lung Infection(Nolan, Saa)

CONCLUSION

The following are our guidelines for use of the newer agents. In the young or middle-aged adult with communityacquired typical pneumonia, who is a normal host and has a Gram stain compatible with pneumococcal pneumonia, the drug of choice is penicillin G. In community-acquired atypical pneumonia in a patient with the same scenario, the drug of choice is erythromycin. For treatment of community-acquired pneumonia in a complicated host, te, the elderly or nursing home patient, the patient with chronic lung disease, the alcoholic, or the patient who has recently had influenza, we recommend cefuroxime for initial empiric antibiotic coverage. The patient with hospital-acquired pneumonia can present in one of three settings. The first is the patient with known airway colonization with Gram-negative rods, typically a ventilated patient, and where Staphylococcus is not suspected. Empiric antibiotic coverage would be most appropriate with one of the third generation cephalosporins-cefotaxime, ceftizoxime, ceftriaxone, ceftazidime. The second setting is the patient with known airway colonization with Pseudomonas, Serratia, or Enterobacter. Early empiric therapy should probably involve two drugs in this situation. The third generation cephalosporin of choice would be ceftazidime. In the patient with normal renal function, this should be combined with aminoglycoside. The third setting is the suspected Staphylococcus or anaerobic infection in the hospitalized patient. Ticarcillin-clavulanate or ampicillin-sulbactam are reasonable first-line drugs until an etiologic diagnosis can be established. Another situation in which the newer agents are to be considered is pneumonia where the etiologic agent is documented to be a sensitive Gram-negative isolate. In these situations, aztreonam or ciproHoxacin may be appropriate. In the patient who has a multidrugresistant isolate sensitive only to imipenem, imipenem plus an aminoglycoside would be a reasonable choice. Some of these newer agents will also be useful in chronic lung disease. For exacerbation of cystic fibrosis, ceftazidime, imipenem, aztreonam, or ciprofloxacin could all be used with selection based on rotation of

antibiotics and culture and sensitivity data. Situations where empiric courses of therapy for exacerbations of chronic obstructive pulmonary disease are given, it is reasonable to add ciproHoxacin to our oral armamentarium of empiric therapy with tetracycline, ampicillin, TMP-SMX, cefaclor, and erythromycin. In the renal transplant patient or AIDS patient with CMV pneumonitis, ie, with histopathologic findings of CMV inclusions or DNA hybridization studies positive for CMV DNA with positive CMV culture, DUPG should be instituted. This review of new drugs for treating lung infection has included 14 agents. Only one representative from each of three new classes of antimicrobials is currently available for use in adult lower respiratory infection. Development is just beginning among the carbapenems, monobactarns, and quinolones. New drugs in each class will surely continue to make an impact on the treatment of lung infection. Since we first began to influence the course of pneumonia with penicillin in the 194Os, the spectrum of pathogens and therapeutic options has become more and more complex. In 1988, there is no looking back to the simpler days when the only choice lay between penicillin or erythromycin for treating lung infection. REFERENCES

1 Meyers BR. Treatment of adult pneumonia and bronchitis with cefuroxime sodium: a clinical review In: Moellering RC t ed. The clinical significance of the newer beta-Iactam antibiotics: focus on cefuroxime. New York: ADIS Press, 1983:89-98 2 Pines A, Raatat H, Khorasani M, Mullinger BM. Cefuroxime and ampicillin compared in a double-blind study in the treatment of lower respiratory tract infections. Chemotherapy 1981; 27:459-65 3 Mehtar S, Parr JH t Morgan OJ. Comparison of cefuroxime and cotrimoxazole in severe respiratory tract infection. Antimicrob Agents Chemother 1982; 9:479-84 4 Schentay JJ, Vari AJ, Winslade NEt Swanson DJ, Smith IL, Simmons G~ et ale Treatment with aztreonam or tobramycin in critical care patients with nosocomial Gram-negative pneumonia. Am J Med 1985; 78:34-41 5 Lode H t Wiley Rt Hoftken c, Wagner}, Bomer K. Prospective randomized controlled study of ciproBoxacin versus imipenemcilastatin in severe clinical infections. Antimicrob Agents Chemother 1987; 31:1491-96 6 O'Brien RJt Lyle MAt Snider DE. Rifabutine (Ansamycin LM 427): a new rifamycin-S derivative for the treatment of mycobacterial diseases. Rev Infect Dis 1987; 9:519-30

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